Grassart Alexandre, Dujeancourt Annick, Lazarow Paul B, Dautry-Varsat Alice, Sauvonnet Nathalie
Institut Pasteur, Unité de Biologie des Interactions Cellulaires, CNRS URA 2582, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France.
EMBO Rep. 2008 Apr;9(4):356-62. doi: 10.1038/embor.2008.28. Epub 2008 Mar 14.
There are several endocytic pathways, which are either dependent on or independent of clathrin. This study focuses on a poorly characterized mechanism-clathrin- and caveolae-independent endocytosis-used by the interleukin-2 receptor beta (IL-2R beta). We address the question of its regulation in comparison with the clathrin-dependent pathway. First, we show that Ras-related C3 botulinum toxin substrate 1 (Rac1) is specifically required for IL-2R beta entry, and we identify p21-activated kinases (Paks) as downstream targets. By RNA interference, we show that Pak1 and Pak2 are both necessary for IL-2R beta uptake, in contrast to the clathrin-dependent route. We observe that cortactin, a partner of actin and dynamin-two essential endocytic factors-is required for IL-2R beta uptake. Furthermore, we find that cortactin acts downstream from Paks, suggesting control of its function by these kinases. Thus, we describe a cascade composed of Rac1, Paks and cortactin specifically regulating IL-2R beta internalization. This study indicates Paks as the first specific regulators of the clathrin-independent endocytosis pathway.
存在几种内吞途径，它们要么依赖网格蛋白，要么不依赖网格蛋白。本研究聚焦于一种特征不明的机制——白细胞介素-2受体β（IL-2Rβ）所采用的不依赖网格蛋白和小窝的内吞作用。我们探讨了与依赖网格蛋白的途径相比，其调控问题。首先，我们表明Ras相关的C3肉毒杆菌毒素底物1（Rac1）是IL-2Rβ进入细胞所特需的，并且我们确定p21激活激酶（Paks）为下游靶点。通过RNA干扰，我们表明与依赖网格蛋白的途径不同，Pak1和Pak2对于IL-2Rβ的摄取都是必需的。我们观察到，肌动蛋白结合蛋白cortactin——肌动蛋白和发动蛋白这两个重要内吞因子的结合蛋白——对于IL-2Rβ的摄取是必需的。此外，我们发现cortactin在Paks的下游起作用，提示这些激酶对其功能的控制。因此，我们描述了一个由Rac1、Paks和cortactin组成的级联反应，它特异性地调控IL-2Rβ的内化。本研究表明Paks是不依赖网格蛋白的内吞途径的首个特异性调控因子。
